The primary aim of this project is to characterize the location of the subcortical and white matter lesions and to evaluate its impact on relevant cognitive function and on brain regions critical to the mood circuit. Using 3D images acquisition and recently developed topographic analysis (developed for studying multiple sclerosis lesions) we plan to carefully evaluate the location of the lesions relative to controls. We will also use recently developed image analytic methods to produce maps of lesions as they relate to specific features of the illness. We will also evaluate volumetric changes in prefrontal cortex, amygdala, and basal ganglia to see if these lesions impact on these structures (i.e., evidence for circuit disruption). In the same subjects we will obtain diffusion tensor image to identify white matter tracts and the location of the damage relative to these white matter tracts. These will be evaluated in relation to tests of cognitive function of relevant regions of the brain. This project will shed light on the nature and location of some of the disruptions of the circuits described earlier. This project does not overlap with any existing project and the techniques developed in the context of this study will be useful for other projects. This project will lead to significant innovation in the development of new imaging techniques and assessment tools. The results of the project should greatly aid our understanding of the neuroanatomical substrates of depression.